CN109893518A - Polyunsaturated long-chain ketone or its salt are preparing the purposes in the drug for treating rheumatoid arthritis - Google Patents

Polyunsaturated long-chain ketone or its salt are preparing the purposes in the drug for treating rheumatoid arthritis Download PDF

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Publication number
CN109893518A
CN109893518A CN201811592300.8A CN201811592300A CN109893518A CN 109893518 A CN109893518 A CN 109893518A CN 201811592300 A CN201811592300 A CN 201811592300A CN 109893518 A CN109893518 A CN 109893518A
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compound
group
ring
disease
cell
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阿斯特丽德·尤鲁姆斯特罗福伊尔黑尔姆
贝丽特·约翰森
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Coegin Pharma AS
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Avexxin AS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/121—Ketones acyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/131—Amines acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups

Abstract

The present invention relates to polyunsaturated long-chain ketones or its salt to prepare the purposes in the drug for treating rheumatoid arthritis.The present invention relates to the compound or its salts of following formula to prepare the purposes in the drug for treating rheumatoid arthritis:Wherein X is CF3。

Description

Polyunsaturated long-chain ketone or its salt are being prepared for treating rheumatoid arthritis Purposes in drug
The application be the applying date be on 09 01st, 2011 it is entitled " utilize polyunsaturated long-chain ketone rheumatoid close The divisional application of the Chinese patent application No.201180052040.5 of the scorching treatment of section ".
Technical field
The present invention relates to certain polyunsaturated long-chain ketones in treatment rheumatoid arthritis and other chronic auto-immunes Application in disease, and in particular to the position α in such treatment in carbonyl functional group (functionality) takes with electrophilic The ketone of Dai Ji.
Background technique
The present inventor seeks the novel method for the treatment of for rheumatoid arthritis (RA) and associated disease.Rheumatoid closes Saving scorching (RA) is acquired, chronic, systemic inflammatory disease, mainly influences the synovial membrane in the multiple joints of body.In RA, it is immunized Synovial membrane is attacked to system mistake, and chronic inflammation later causes arthralgia, stiff, swelling and the forfeiture of function of joint (passing through cartilage and bone destruction).Only in the U.S., rheumatoid arthritis is just influenced more than two million peoples.There are no obtain completely Know the interaction of the heredity, immunogenicity and environmental factor that cause RA, and causes and arthritic antigen is caused not yet to determine.No Its origin is managed, antigenic activation CD4+ T helper cell generates the cell factor that can activate intra-articular various cells, and stimulation is scorching Disease and degradation.
After making a definite diagnosis synovitis, pass through the acid mediated autocrine of cell factor and other inflammatory mediators such as quasi-eicosane With paracrine signal network, disease is promoted to there is (perpetuation) and joint injury (destruction) for a long time.
In RA, the damage of articular cartilage and bone involves inflammatory cytokine TNF and interleukin-1 B (IL-1B).In morning In phase RA, chronic synovitis leads to soft tissue swelling, thin due to oedema, synovial cell proliferation and proliferation and immunocompetence The infiltration of born of the same parents.With the development of synovitis, inflammatory tissue agglomerate diffuses to articular surface, is formed under synovial membrane and cartilage or cartilage Bone interface at pannus (pannus).From pannus, neutrophil leucocyte and synovial cell penetrate cartilage or bone surface, cause The maturation and activation of osteoclast and cartilage cell.The synovial cell of activation is by secreting various protease, including matrix metal Protease (MMP) directly promotes joint injury, and is converted into decomposing state from synthetic state by Induction of chondrocytes phenotype, Lead to the forfeiture and damage of cartilage.Articular cartilage and bone degradation with the development of RA, below pannus.Finally, pannus Joint space is filled, fibrosis, calcification and finally permanent tetanic are caused.
Therefore, in RA pathology, inflammation plays an important role.Prostaglandin E2 (the PGE in RA2) acutely increase with And reduce PGE2The beneficial anti-inflammatory and pain effect of synthesis are well known.The numerator mediated object of the early and middle portion of inflammation includes swollen Tumor necrosis factor α (TNF-α), interleukin I L-1, IL-6, IL-8 and IL-15, transforming growth factor β, Desmocyte growth factor Son and platelet derived growth factor.After determining inflammatory reaction, synovial membrane is thickened, cartilage and lower layer bone (underlying Bone) start to decompose, and the evidence of joint injury generates.
In the proliferation of RA, synovioblast is also key cells.These cells seemingly local pathogenic event Core.After the activation, rheumatoid arthritis synovial fibroblast generates various cell factors, chemotactic factor (CF) and matrix Degrading enzyme mediates the interaction with adjacent inflammatory and endothelial cell.These interactions cause cell in synovia Undue growth (synovial hyperplasia) causes the progressive of cartilage and bone to damage.
For rheumatoid arthritis, without known cure method, but many types treatment can alleviate symptom and/ Or change the process of disease.There are two aspects for the purpose for the treatment of: alleviating the further deterioration of current symptom and prevention joint. In general, reaching for latter purpose is can be supplemented with other medicines such as by means of Disease Modifying Anti-Rheumatic drug (DMARD) Anti-inflammatory or analgesic drug product.
Nonsteroidal anti-inflammatory drug (NSAID) has been used for the treatment of RA for a long time.NSAID mitigates pain, fever, and higher Mitigate inflammation under dosage.The mechanism of action of NSAID be usually directed to inflammation part inhibit cyclooxygenase (cyclooxegenase, COX).Therefore, when for when treating RA, it is generally recognized that NSAID does not have anti rheumatism action.However, certain NSAID, such as fill in It examines former times, has been reported through the Apoptosis inhibitor synovial hyperplasia for inducing synovioblast.
In addition to NSAID and DMARD, the most successful therapeutic agent for RA patient is TNF neutralizing antibody.However, biological Preparation (for example, monoclonal antibody of TNF and IL-6 receptor and recombinant soluble TNF receptor etc.) may have adverse side effect, Including reduced resistance, the cancer development and for the immunity of biopharmaceuticals itself to infection.
As in from the discussion above it can be clearly seen that arthritic pathology is complicated and is permitted involved in the disease Multi-tracer.However, inflammation plays an important role in illness as many Other diseases.The present inventor seek for The replaceable therapy of RA, independent of NSAID or other known treatment method.
Present inventors have recognized that compound claimed herein have treat general chronic inflammation disease with And the potentiality of especially rheumatoid arthritis.It has been found by the present inventors that certain form of based on long-chain unsaturated fatty acid point The compound of son can be used for treating rheumatoid arthritis.It is various to show that the compound of the present invention has for we in embodiment Beneficial property, for example, relative to Markers of inflammation PGE2, COX2 and IL-8.It is appreciated that in rheumatoid joint of the invention In inflammation nursing, the inhibition of these markers can bring benefit.
Present inventors have recognized that these compounds and other compounds can also be used for treatment rheumatoid arthritis or its Its chronic inflammation disease.
Summary of the invention
Therefore, according on one side, the present invention provides the compounds of formula (I), for treating rheumatoid arthritis:
R-L-CO-X (I)
Wherein R is optionally by one or more hetero atoms or the intermittent C of heteroatom group10-24Unsaturated alkyl, wherein One or more hetero atoms or heteroatom group are selected from S, O, N, SO, SO2, the alkyl includes at least four unconjugated double bond；
L is linking group, and the bridging of 1 to 5 atom is formed between R base and carbonyl CO；And
X is electron-withdrawing group.
The present invention also provides a series of new compounds.According on the other hand, the present invention provides formulas (II) Compound:
R-L1-CO-X (II)
Wherein R and X is as defined above；
L1 is linking group, forms the bridging of 1 to 5 atom between R base and carbonyl CO, forms the linking group Main chain atom be selected from carbon and/or hetero atom N, O, S, SO, SO2；
Wherein linking group L1 includes the ring in main chain, or linear, and the backbone atoms of linking group by At least one side chain, which replaces, (removes SO or SO2Any oxygroup except).
According on the other hand, the present invention provides a kind of method for treating rheumatoid arthritis, this method includes will The compound of a effective amount of formula (I) or (II) as described above gives animal, preferably mammal, such as people.
According on the other hand, the present invention provides the compounds of formula as described above (I) or (II) to be used in preparation Treat the application in the drug of rheumatoid arthritis.
Also contemplating the compound of the present invention can be used for treating general chronic inflammation disease, preferably super with type III The autoimmune disease of quick property.Especially, which can be used for treating chronic inflammation disease or synovial disease.Therefore, According on the other hand, the present invention provides the compounds of formula (I), for treating chronic autoimmune disease, preferably have III The autoimmune disease or chronic inflammation disease or synovial disease of type hypersensitivity:
R-CO-X (I)
Wherein R is optionally by one or more hetero atoms or the intermittent C of heteroatom group10-24Unsaturated alkyl, wherein One or more hetero atoms or heteroatom group are selected from S, O, N, SO, SO2, the alkyl includes at least four unconjugated double bond；With And
X is electron-withdrawing group.
According on the other hand, the present invention provides a kind of method for treating autoimmune disease, the autoimmune diseases It is preferred that autoimmune disease or chronic inflammation disease or synovial disease with type III hypersensitivity, this method includes will be effective The compound of the formula (I) or (II) as described above of amount gives animal, preferably mammal, such as people.
According on the other hand, the present invention provides the applications of formula as described above (I) or the compound of (II), are used for Preparation for treating autoimmune disease, autoimmune disease or chronic inflammation disease preferably with type III hypersensitivity or The drug of synovial disease.
The present invention relates to the compounds of formula (I) in treatment rheumatoid arthritis and associated disease and chronic inflammation disease Application in disease and synovial disease.
Group R preferably comprises 5 to 9 double bonds, preferably 5 to 8 double bonds, for example, 5 to 7 double bonds such as 5 or 6 double bonds.This A little keys should be unconjugated.It is also preferred that double bond is not conjugated with carbonyl functional group.
The double bond present in group R can have cis or trans configuration, however, it is preferred that existing major part Double bond (i.e. at least 50%) has cis-configuration.In further advantageous embodiment, all double bonds in group R all have There is cis-configuration, or other than the double bond near carbonyl can have anti-configuration, all double bonds all have cis- structure Type.
Group R can have 10 to 24 carbon atoms, preferably 12 to 20 carbon atoms, especially 17 to 19 carbon atoms.
Although R base can be interrupted by least one hetero atom or heteroatom group, this is not preferred, and R base master Chain preferably only includes carbon atom.
R base can have up to three substituent groups, for example, being selected from halogen, Cl-6Alkyl, such as methyl, C1-6Alkoxy.Such as Fruit exists, and substituent group is preferably nonpolar and lesser, such as methyl.However, it is preferred that R base is still unsubstituted.
R group is preferably linear.It is preferably derived from natural origin such as long chain fatty acids or ester.Especially, R base can be with source In AA, EHA or DHA.
L is linking group, and the bridging of 1 to 5 atom is formed between R base and carbonyl CO.Linking group L is provided in R 1 to 5 backbone atoms between base and carbonyl, the bridged group of preferably 2 to 4 backbone atoms.In attachment (linker) Atom in main chain can be carbon and/or hetero atom such as N, O, S, SO, SO2.Atom can form the part of ring and linker The backbone atoms of group can be replaced by side chain, for example, by C1-6Alkyl, oxygroup, alkoxy or halogen.
The object that preferably constitutes of linking group is-CH2-、-CH(C1-6Alkyl)-,-N (C1-6Alkyl)-,-NH- ,-S- ,-O- ,- CH=CH- ,-CO- ,-SO- ,-SO2, linking group can sequentially be connected to each other to form with any (chemistry is significant). Therefore, by using two methylene and-S- a group, attachment-SCH is formed2CH2-。
It is highly preferred that linking group L includes at least one hetero atom in main chain.It is also preferred that being connected to R First backbone atoms of the linking group of group are hetero atom or heteroatom group.
It is highly preferred that linking group L is included at least one of main chain-CH2Connection.It is desirable that adjacent to carbonyl The atom of the linking group of base is-CH2-。
Preferably, group R or group L (size depending on L base) provides the position α, β, γ or δ for being located at carbonyl, preferably β or γ hetero atoms or heteroatom group of carbonyl.Preferably, hetero atom is O, N or S or sulfur derivatives such as SO.
Therefore, in fact it is highly preferred that linking group be-NH2CH2、-NH(Me)CH2-、-SCH2-、-SOCH2-、-COCH2-。
Linking group is ring or also belongs to the present invention comprising ring.Thus, for example, attachment can be thiophene, such as 2,4- Thiophene provides the bridging (passing through shortest path) with two atoms of carbonyl.Attachment can also be ring, such as furans, tetrahydro Furans, piperidines, hexamethylene, benzene or pyridine.In the case where attachment includes ring, it is preferred that ring is 5- or 6-membered ring.It is preferred that , above-mentioned ring includes at least one hetero atom or heteroatom group.Preferably, ring is unsaturated ring or aromatic ring.As R and When COX group is directly connected in above-mentioned ring, it is preferable that R base and COX group are connected on not homoatomic, and preferably, they It is connected on the carbon atom of ring.
It is preferred that such substitution mode so that R and carbonyl substituent group be relative to each other alpha, gamma position (that is, 1,3 or 2,4 or 3,5- separates (split)).
For the avoidance of doubt, it should be highlighted that, the bridging of 1 to 5 atom should be regarded as most short to carbonyl since attachment Path.
In conjunction with the discussion of following L1, suitable ring attachment is shown below.
Include ring and acyclic portion, such as CH2Thiophene or NH2The attachment of thiophene etc. is also within the scope of the invention.? In such attachment, it is preferable that R base is connected directly to ring, and carbonyl is connected to acyclic portion, for example,-CH2Key connects. Technical staff will find out the different attachments for being suitable for the invention all kinds.
Highly preferred linker is-CH2-、-CH2-CH2-、-CH(Me)、-CH(Me)CH2-、-CH(Me)-CH(Me)-、 SCH2、NHCH2、N(Me)CH2, 2,4- thiophene and 2,5- thiophene.
In the compound of chemical formula (II), linking group L1 is linking group, forms 1 between R base and carbonyl CO To the bridging of 5 atoms, the atom for forming the main chain of the linking group is selected from carbon and/or hetero atom N, O, S, SO, SO2, Middle linking group L1 includes the ring in main chain, or linear, and the backbone atoms of linking group are by least one side Chain, which replaces, (removes SO or SO2Any oxygroup except).
Linking group L1 is preferably provided at the main chain of 2 to 4 backbone atoms between R base and carbonyl.
When main chain is linear (that is, it does not include ring structure), at least one atom in main chain has side chain. In addition to oxygroup, side chain can reside in SO or SO2On group.Suitable side chain includes C1-6Alkyl, oxygroup in addition, alcoxyl Base, NH2、N(C1-6Alkyl) H, N (C1-6Alkyl)2Or halogen.
Such side chain is preferably connected to the hetero atom in the main chain of attachment L1.Preferably, adjacent to the master of carbonyl Chain atom is not branch.
It is desirable that should there is only a side chains.
The object that preferably constitutes of linking group is-CH2-、-CH(C1-6Alkyl)-,-N (C1-6Alkyl)-,-NH- ,-S- ,-O- ,- CH=CH- ,-CO- ,-SO- ,-SO2, linking group can sequentially be connected to each other to form with any (chemistry is significant), The requirement of at least one side chain in L1 group is expected simultaneously.
It is highly preferred that linking group L1 includes at least one hetero atom in main chain.It is also preferred that being connected to The first backbone atoms of the linking group L1 of R base are hetero atom or heteroatom group.
It is highly preferred that linking group L1 is included at least one of main chain-CH2Connection.It is desirable that adjacent to The atom of the linking group of carbonyl is-CH2-。
Highly preferred linearly connected group L1 is-NH (Me) CH2-。
Ring or the ring-containing linker of packet are also within the scope of the invention.In order to make linking group include ring, above-mentioned ring is necessary It is opposite with the side chain except mainly connection atom really as the part of attachment or attachment.
Thus, for example, attachment can be thiophene, for example, 2,4- thiophene, provide the bridging with two atoms of carbonyl (passing through shortest path).Attachment can also be ring, such as furans, tetrahydrofuran, piperidines, hexamethylene, benzene or pyridine.In attachment In the case where ring, it is preferable that ring is 5- or 6-membered ring.Preferably, ring includes at least one hetero atom or heteroatom group.
Preferably, ring is unsaturated ring or aromatic ring.When R and COX group is connected directly to such ring, it is preferable that R base It is connected on not homoatomic with COX group, it is also preferred that they are connected on the carbon atom of ring.
It is preferred that such substitution mode so that R and carbonyl substituent group be relative to each other alpha, gamma position (that is, 1,3 or 2,4 or 3,5- separation).Atom number in the main chain of linking group will connect the most short of R and CO portion by the ring in molecule Path determines.
It shown below suitable ring attachment, wherein R base and carbonyl can connect any carbon atom to these rings Or available nitrogen-atoms:
Comprising ring and acyclic portion, for example, CH2Thiophene or NH2The attachment of thiophene etc. is also within the scope of the invention. In such attachment, it is preferred that R base is connected directly to ring, and carbonyl is connected to acyclic portion, for example,-CH2Key Even.In the case where attachment includes loop section, then do not need to make any acyclic portion with side chain.
Highly preferred linking group L1 is-CH (Me) ,-CH (Me) CH2-、-CH(Me)-CH(Me)-、N(Me)CH2、2, 4- thiophene and 2,5- thiophene.
Group X is electron-withdrawing group.In this regard, suitable group includes O-C1-6Alkyl, CN, OCO2-C1-6Alkyl, Phenyl, CHal3、CHal2H、CHalH2, wherein Hal indicates halogen, for example, fluorine, chlorine, bromine or iodine, preferably fluorine.Especially, electricity is inhaled Subbase group is CN, phenyl, CHal3、CHal2H、CHalH2, wherein Hal indicates halogen, such as fluorine, chlorine, bromine or iodine, preferably fluorine.
In a preferred embodiment, electron-withdrawing group is CHal3, especially CF3。
Therefore, according on the other hand, the present invention provides the compounds of formula (III), for treating disease described herein Disease:
R-Y1-Y2-CO-X (III)
Wherein R and X is as defined above；
Y1 is selected from O, S, NH, N (C1-6Alkyl), SO or SO2；And
Y2 is (CH2)nOr CH (C1-6Alkyl)；Or
Y1 and Y2 is formed together 5- or 6-membered carbocyclic ring or heterocycle, optionally unsaturated ring or aromatic ring；Or
Y1 forms 5- or 6-membered carbocyclic ring or heterocycle, optionally unsaturated ring or aromatic ring, and Y2 is (CH2)n；
Wherein n is 1 to 3, preferably 1.
It shown below for highly preferred compound of the invention:
As described above, certain compounds are new and form further aspect of the present invention.
Therefore, according on the other hand, the present invention provides the compounds of formula (IV):
R-Y3-Y4-CO-X (IV)
Wherein R and X is as defined above；
Y3 and Y4 is formed together 5- or 6-membered carbocyclic ring or heterocycle, saturated rings, unsaturated ring or aromatic ring；Or
Y3 forms 5- or 6-membered carbocyclic ring or heterocycle, saturated rings, unsaturated ring or aromatic ring, and Y4 is (CH2)n；
Wherein n is 1 to 3, preferably 1.
Further new compound includes the compound of formula (V):
RN(C1-6Alkyl) (CH2)nCOX (V)
Wherein R, n and X are as defined above, especially following compounds:
Further preferred new compound is that wherein L1 group is ring or comprising those of ring compound.
It shown below the preferred compound of formula (II):
Wherein n is 1 to 3, such as 1 to 2.
Especially preferably, above-mentioned group is connected to 2 and 4 of ring (wherein atom 1 is S atom).
According on the other hand, the present invention provides a kind of pharmaceutical compositions, and it includes as defined above any new Compound and at least one pharmaceutical excipient combination.
In the conceived case, can be in the form of salt, solvate, prodrug or ester, the form of especially salt gives this The compound of invention.It is preferable, however, that not using such form.
In general, can easily prepare pharmaceutical salts by using desired acid.Salt can precipitate and pass through from solution Filter collects or can be by evaporating solvent recovery.For example, the compound of formula (I) being added such as the aqueous solution of hydrochloric acid in acid Aqueous suspension simultaneously evaporates the mixture of generation to drying (freeze-drying) to obtain the acid-addition salts as solid.Alternatively, may be used The compound of formula (I) is dissolved in suitable solvent, such as alcohol such as isopropanol, same solvent or other conjunctions can be added an acid to In suitable solvent.Then can add directly or by a small amount of polar solvent such as diisopropyl ether or hexane is added to precipitate the acid of generation At salt, and it is isolated by filtration.
Suitable addition salts are formed by inorganic acid or organic acid, these acid formed non-toxic salts, example be hydrochloride, Hydrobromate, hydriodate, sulfate, disulfate, nitrate, phosphate, hydrophosphate, acetate, trifluoroacetate, horse Come hydrochlorate, malate, fumarate, lactate, tartrate, citrate, formates, gluconate, succinate, third Ketonic acid salt, oxalates, oxaloacetate, trifluoroacetate, sugar lime, benzoate, alkyl or aryl sulfonate (such as methylsulphur Hydrochlorate, esilate, benzene sulfonate or tosilate) and isethionate.Representative example includes trifluoroacetate And formates, such as two (trifluoroacetates) or three (trifluoroacetates) and single formates or diformate, especially three (trifluoros Acetate) or two (trifluoroacetates) and single formates.
It can use the compound of known chemical synthesis route preparation formula (I).It is expedient to the compound flower commercially available from Raw tetraenoic acid (AA), EPA (20-5,8,11,14,17- five olefin(e) acid of complete-Z-) or DHA (complete-Z- 22-4,7,10,13, 16,19- acid) start to synthesize.For example, by the way that carboxylic acid is converted to its corresponding acid chloride, and make in the presence of pyridine Above-mentioned acid chloride and trifluoroacetic acid anhydride reactant, easily can be converted to such as-COCF for the acid functional group of these compounds3Base Group.
It is also easy to realize and hetero atom is introduced into carbochain.Easily, for example, starting acid is reduced into alcohol, and, if needed It wants, is converted into corresponding mercaptan.It is then possible to make nucleophilic thiol and group such as BrCH2COCF3Reaction, thus introduce carbonyl and Electrophilic species.Complete synthetic schemes may refer to J.Chem.Soc., Perkin Trans 1,2000,2271-2276 or J.Immunol.,1998,161,3421。
In the case where the main chain of molecule includes nitrogen-atoms, interchangeable synthetic method is needed.It can use above The scheme provided in the paper of Perkin Trans realizes the formation of how unsaturated alcohol.Thereafter, alcohol-OH is to-NH2, for example, benzene is adjacent The conversion of dicarboximide and the reduction of subsequent hydrazine, make it possible to form-NH2CH2COCF3Group, wherein by with trifluoro ring Oxypropylene (TFPO) reacts and hydroxyl is oxidized to ketone.The reaction shows as follows.
Herein reaction before, by formed N-BOC group and, for example, with lithium aluminium hydride reduction, the first of nitrogen can be carried out Base.With TFPO react and oxidation obtains attachment NMe-CH2。
This forms another aspect of the present invention, thus provides the method that one kind is used to prepare the compound of formula (I), wraps It includes:
(I) compound R-OH is converted to R-NH2；
(II) N atom is optionally made to methylate；
(III) it is reacted with TFPO；And
(IV) hydroxyl of formation is oxidized to ketone.
It is proposed that the compound of the present invention is mainly used for the treatment of especially rheumatoid arthritis.
Treatment refers to following at least one:
(i) prevent or delay the appearance of the clinical symptoms of the disease developed in mammals；
(ii) inhibit disease, that is, prevent, slow down or postpone disease development or its recurrence or its its at least one clinic or Inferior clinical symptom, or
(iii) alleviate or weaken one or more clinical or inferior clinical symptoms of disease.
Benefit for subject to be treated is statistically significant or patient or doctor is at least perceived. In general, technical staff can discover when " treatment " occurs.
Term " treatment " herein, which is also used to cover preventative smelting, to be treated, i.e. treatment has the wind for developing inquired into disease The subject of danger.
The compound of the present invention can be used for any animal subjects, especially mammal, more particularly people or serve as The animal (for example, mouse, monkey etc.) of the model of disease.
In order to treat disease, need to give a effective amount of activating agent to patient." therapeutically effective amount " refers to the amount of compound, This kind for the treatment of is set to tell on for being enough when treating symptom, obstruction and illness when giving animal." therapeutically effective amount " will have Institute is different, depends on compound, disease and its severity and age, weight, physical condition and the sound of subject to be treated It answers, and will finally be determined by attending physician.
Although can be used as the change of cake mass (bulk substance) giving construction I in order to for method of the invention Object is closed, but it is preferred that active component is provided with pharmaceutical preparation, for example, its Chinese medicine and basis give approach and standard pharmaceutical The selected pharmaceutical carrier mixing of practice.
Term " carrier " refers to the diluent, excipient and/or carrier that reactive compound is given using it.Medicine of the invention Compositions may include the combination of more than one carrier.These pharmaceutical carriers can be sterile liquid, as water, saline solution, Dextrose hydrate solution, aqueous glycerol solution, and oil comprising petroleum, animal oil, vegetable oil or synthesis source oil, such as Peanut oil, soybean oil, mineral oil, sesame oil etc..It is preferred that water or aqueous solution, saline solution and dextrose hydrate and glycerol are molten Liquid is used as carrier, it is especially useful in injection solution." Remington's of the suitable pharmaceutical carrier description in E.W.Martin In Pharmaceutical Sciences " (the 18th edition).It can be carried according to approach of giving and standard pharmaceutical practice selection drug Body.In addition to carriers, pharmaceutical composition may include any suitable adhesive, lubricant, suspending agent, smears, and/or increasing Solvent.
" pharmaceutical excipient " refers to a kind of excipient, which can be used for preparing pharmaceutical composition, usually safe, Nontoxic and not biology or other aspects are undesirable, and including can be used for veterinary purpose and human pharmaceutical use Excipient.As used in this application, " pharmaceutical excipient " includes a kind of and more than one such excipient.
It should be understood that pharmaceutical composition used according to the invention can be oral, parenteral, percutaneous, sucking, sublingual, office Portion, infusion, nose or intestines form give (or other mucous membranes are given) suspension, capsule or tablet, can in a usual manner and Utilize one or more pharmaceutical carriers or excipient.
There may be different composition/formulation requirements, depend on different delivery systems.Equally, if composition Comprising more than one active constituent, then those ingredients can be given by identical or different approach.
Pharmaceutical preparation of the invention, which can be, is suitable for oral, mucous membrane and/or the liquid parenterally given, for example, drops, Agent, solution, Injectable solution are starched, is prepared for (ready for use) i.e. or by dilution refrigeration dry products, but excellent Select solid or semisolid, as tablet, capsule, granule, powder, fine granule, vaginal suppository, suppository, cream, ointment, Gelling agent, ointment or solution, suspension, emulsion or the other forms suitable for passing through cutaneous routes or being given by sucking.
The compound of the present invention can be given, for immediately, delay, adjust, continue, interval (pulse) or controlled release Using.
In one aspect, Orally administered composition is slowly, postpones or position release (for example, enteron aisle, especially colon are released Put) tablet or capsule.Without limitation, this releasing pattern (profile) can be accomplished by the following way: making With the coating of condition in tolerance stomach, and content is discharged in the other parts of colon or gastrointestinal tract, wherein lesion has been determined Or perhaps sustained release can be realized by simply slowing down the coating of decomposition or a kind of or more by selecting inflammation part The appropriate coating of kind and other excipient, can be in such a way that single formulation combines both (delay and positioning releases).Such system Agent constitutes further aspect of the present invention.
Proper combination and/or casing oral preparation for postponing or positioning release include Formulation film, which applies Be furnished with following material: it is water-fast, pH is sensitive, by intestinal juice digest emulsify or when wetted with slow but regular rate It falls off.Suitable coating material includes, but are not limited to hydroxypropyl methyl cellulose, ethyl cellulose, cellulose acetate neighbour benzene two Formic acid esters, Opaseal, hydroxypropyl methylcellulose phthalate, methacrylic acid and its ester Polymer and their combination.Plasticizer can be used, e.g., but be not limited to, polyethylene glycol, dibutyl phthalate, three Acetin (triacetin) and castor oil.Pigment can be also used for colouring film.By preparing bolt using carrier such as cocoa butter Agent, suppository base such as Suppocire C and Suppocire NA50 are (by Gattefosse Deutschland GmbH, D- Weil am Rhein, Germany supply) and other Suppocire type excipient, it is by hydrogenated palm oil and palm core The interesterification of oily (C8-C18 triglycerides), glycerol and special fatty acid or polyglycosylated glyceride and What the esterification of whitepsol (the hydrogenated vegetable oil derivative comprising additive) obtained.By using according to the present invention Reactive compound appropriate and solvent or excipient enema for suspension.By using micronization compound and Suitable carrier prepares suspension, wherein above-mentioned carrier includes suspension stabilizer, thickener and emulsifier, such as carboxymethyl cellulose and Its salt, polyacrylic acid and its salt, carboxyl vinyl polymer and its salt, alginic acid and its salt, propylene glycol alginate, chitosan, Hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methylcellulose, polyvinyl alcohol, gathers at hydroxypropyl methyl cellulose Vinylpyrrolidone, N- vinylacetyl amine polymer, polyethylene methacrylate, polyethylene glycol, pluronic, gelatin, Methyl vinyl ether-maleic acid copolymer, soluble starch, amylopectin and methyl acrylate and 2- ethylhexyl propylene The copolymer of acid esters lecithin, lecithin derivative, methyl glycol fatty acid ester, fatty acid glyceride, sorbitan fatty acid ester, Polyoxyethylene sorbitol aliphatic ester, cithrol, polyoxyethylene hydrated castor oil (polyoxyethylene Hydrated caster oil), the buffering appropriate of polyoxyethylene alkyl ether, pluronic and pH value in 6.5 to 8 ranges System.The use of preservative, screening agent is suitable.The average diameter of micronized particle can be 1 to 20 micron, or can be Less than 1 micron.Compound can also be incorporated in preparation by using their Water-soluble salt forms.
Alternatively, it is possible to material be incorporated to the matrix (matrix) of tablet, for example, hydroxypropyl methyl cellulose, ethyl The polymer of cellulose or acrylate and methacrylate.It can also be coated with by compression, subsequent material is applied to Tablet.
Pharmaceutical composition can be prepared by mixing the active material of therapeutically effective amount with pharmaceutical carrier, wherein above-mentioned Pharmaceutical carrier can have different form, depend on giving mode.
Pharmaceutical composition can be prepared by using customary pharmaceutical excipients and preparation method.For the oral shape given Formula can be capsule, powder or tablet, wherein common solid carrier include lactose, it is starch, glucose, methylcellulose, hard Fatty acid magnesium, Dicalcium Phosphate, can add mannitol, and common liquid oral excipients include, but are not limited to ethyl alcohol, sweet Oil and water.All excipient can be mixed with disintegrating agent, solvent, granulating agent, humidizer and adhesive.When solid carrier is used for When preparing Orally administered composition, following form: powder, capsule (it includes particle or coated granules), piece is can have but is not limited to The amount of agent, hard capsule or granule and solid carrier can different (1mg to 1g).Tablet and capsule are preferred mouths Oral compositions form.
The example of the medicinal disintegrating agent of Orally administered composition for use in the present invention includes, but are not limited to starch, pregelatinized Starch, sodium starch glycollate, sodium carboxymethylcellulose, croscarmellose sodium, microcrystalline cellulose, alginates/ester, tree Rouge, surfactant, blistering component, hydrated aluminium silicate and crosslinked polyvinylpyrrolidone.
The example that can be used for the medicinal adhesive of the Orally administered composition of this paper includes, but are not limited to Arabic gum；Cellulose Derivative, such as methylcellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose or hydroxyethyl cellulose； Gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, D-sorbite, starch, pregel Change starch, tragacanth, xanthane resin (xanthane resin), alginates, aluminum magnesium silicate, polyethylene glycol or bentonite.
The example of acceptable filler for Orally administered composition includes, but are not limited to lactose, Lactis Anhydrous, one water of lactose Close object, sucrose, glucose, mannitol, D-sorbite, starch, cellulose (especially microcrystalline cellulose), Calcium Phosphate, Dibasic Dihydrate or Anhydrous calcium phosphate, calcium carbonate and calcium sulfate.
The example of the acceptable lubricants of composition for use in the present invention includes, but are not limited to magnesium stearate, talcum, gathers Ethylene glycol, the polymer of ethylene oxide, lauryl sodium sulfate, Stepanol MG, enuatrol, sodium stearyl fumarate, And colloidal silicon dioxide.
The example of suitable medicinal flavoring agent for Orally administered composition includes, but are not limited to synthetic perfume and natural virtue Sesame oil such as oil, flower, the extract of fruit (for example, banana, apple, sour cherry, peach) and their combination and similar fragrance. Their application depends on many factors, and most important factor is to be subjected to the sense organ for the crowd for absorbing the pharmaceutical composition Property.
For Orally administered composition be suitable for medicinal dyestuff example include, but are not limited to synthesis and natural dye such as dioxy Change the extract of titanium, beta carotene and pomelo peel.
The Sutable examples of acceptable sweeteners for Orally administered composition include, but are not limited to aspartame, saccharin, saccharin Sodium, sodium cyclamate, xylitol, mannitol, D-sorbite, lactose and sucrose.The Sutable examples of medicinal buffer include, but unlimited In citric acid, sodium citrate, sodium bicarbonate, disodium hydrogen phosphate, magnesia, calcium carbonate and magnesium hydroxide.
The Sutable examples of medicinal surfactant include, but are not limited to lauryl sodium sulfate and polysorbate.
The Sutable examples of pharmaceutical preservative include, but are not limited to various antibacterial agents and antifungal agent such as solvent, such as second Alcohol, propylene glycol, benzyl alcohol, methaform, quaternary ammonium salt and parabens (such as methyl p-hydroxybenzoate, para hydroxybenzene Ethyl formate, propylparaben etc.).
The Sutable examples of medicinal stabilizer and antioxidant include, but are not limited to ethylenediamine tetra-acetic acid (EDTA), thiocarbamide, Tocopherol and butylated hydroxy anisole.
It may include the pharmaceutical composition of the invention of 0.01 to 99 weight %/active material volume.
The therapeutically effective amount of the compound of the present invention can be determined by methods known in the art.Therapeutically effective amount will take Certainly in the age of patient and general physiological status, used give approach and pharmaceutical preparation.Therapeutic dose will typically about 10 To 2000mg/ days and preferably from about 30 to 1500mg/ days.Other ranges can be used, including, for example, 50-500mg/ days, 50- 300mg/ days, 100-200mg/ days.
Giving can be once a day, twice daily, or more frequent, can reduce in disease or the retention period of obstacle, example Such as, it every two days or replaces once three days daily or twice daily.Dosage will depend on clinical sign with frequency is given, and confirm slow The holding of solution phase, wherein reduce or there is no at least one of acute stage well known by persons skilled in the art or more preferably more than one The clinical sign of kind.
Advantageously, orally or topically giving drug of the invention.
The compound of the present invention can be used for treating rheumatoid arthritis and other general chronic inflammation diseases with And synovial disease and autoimmune disease.Especially, the compound of the present invention can be used for treatingPurpura hypersensitive angiitis, adjuvant arthritis, farmer lung, serum sickness, arthus reaction, is System property lupus erythematosus, subacute bacterial endocarditis and general arthritis and osteoarthritis.
Joint is used for the other known drug of the purpose, and the compound of the present invention can be used for treating rheumatoid joint Inflammation, and this forms further aspect of the present invention.Other useful drugs include Disease Modifying Anti-Rheumatic drug, and antiphlogistic is such as Glucocorticoid or nonsteroidal anti-inflammatory drug, analgestic and pain relief medication.
The present invention is further described referring to following non-limiting embodiment and attached drawing.
Detailed description of the invention
Figure 1A show in the synovial cell for being stimulated proliferation, converging and being broken up with cell factor IL-1 and TNF MMP1, The qPCR measurement of ICAM, IL-6, IL-8, TNF and COX2 expression.
Figure 1B compares the arachidonic release of TNF stimulation SW982 cell.
Fig. 2 shows the PGE after being stimulated 18 hours with TNF, in SW982 cell2Yield.It is monitored by ELISA PGE2Yield.Those cells for receiving treatment are subjected to incubating again with compound 1 (AVX001) or compound 2 (AVX002) (before stimulation) 2 hours.
Fig. 3 A and Fig. 3 B show the PGE that compound 1 and compound 2 in SW982 cell inhibit TNF induction2It generates IC50The measurement of value.100% inhibits to correspond to the PGE for combining ethyl alcohol one to reinstate TNF α induction after incubating 24 hours2It is horizontal.
Fig. 4 shows the dose-dependent inhibition of the IL8 generation using compound 1 (AKH217).With inhibitor precincubation It SW982 cell 2 hours, is stimulated 12 hours with TNF.Control comprising 0.05% ethyl alcohol and 0.05% DMSO, and in highest Same amount of solvent in the inhibitor of concentration.IL8 yield is measured by ELISA.
Fig. 5 shows the variation for converging that ESE-1mRNA is expressed in SW982 cell after three days.Before experimental treatment, Make cell overnight starvation in 0% FCS-DMEM, above-mentioned experimental treatment includes using inhibitor precincubation 2 hours, is then used The TNF of 10ng/ml is stimulated 6 hours.
Fig. 6 shows influence of the compound 2 to the expression of COX2 and IL-8 in TNF stimulation SW982 cell.
Specific embodiment
Embodiment
Following compound is used in an experiment:
Compound 1
Compound 2
In compound 1 and 2, X=CF3
Based on Chem.Soc., Perkin Trans 1,2000,2271-2276 synthesizes these compounds.
Material and method
Reagent
Using converge or spheroidal state (Wada Y, 2005) under cell culture SW982 model cell systems, this be because The [synovial membrane derived from RA is similar to for the gene expression and generation of proinflammatory cytokine.
Stimulation
For stimulation test, by 0.5mL cell suspending liquid (5-7x105A cell/mL) it is seeded in the inner hole of 48 orifice plates. The PBS of exit orifice filling 0.5mL.For the group almost converged, and Incubate cells 1 day (37 DEG C, 5% CO2).After being converged Cell places orifice plate 3 days in the incubator.After this incubative time, the supernatant of 300 μ L is removed and with the stimulation of 50 μ L Culture medium replaces.
Inhibit
Inhibited in the mode similar with stimulation.In inoculation, incubation and with the 0.5%FBS generation in DMEM of 200 μ L After culture medium, the 50 specific inhibitor solutions of μ L (table 1) are added.At 37 DEG C after 2 hours, the supernatant of 50 μ L is removed And it is replaced with above-described 3 kinds of stimulants.
Table 1: the concentration of different inhibitor
Before preparing 50 μM of pre-dilution liquid in the FBS of DMEM/0.5%, by compound 2 and compound 1 96% Ethyl alcohol in dilute (1:50).
PGE2Analysis
PGE2Detection
Slowly melt and dilute (1:1 to 1:2500) sample and control in standard dilution.It is maximum for a step Dilution is 1:10.This is to prepare the reason of several intermediate dilutes are spent.When beginning, all values are measured by duplicate.It is minimum After changing technical error, sample only is analyzed as individual.Other than some small corrections, (such as according to manufacturer's recommendation It is can be found that in the handbook of EIA kit) carry out all further steps.For optimum results, make alkaline phosphatase The incubative time of substrate extends 15 minutes.During incubation, plate is kept in the dark.Sample and control are shown in annex Setting example.After being shaken 10 seconds at 120rpm, under the wavelength of 414 and 595nm, read with Multiscan orifice plate Device (Ascent Labsystems) is read.Corresponding software for obtaining data is the Ascent software of Multiscan, Version 2.4.1。
Data are handled using Microsoft Office Excel 2003 and SigmaPlot 10.0.
Embodiment 1 (reference)
Validity of the TNF and IL1 as the inducer of proinflammatory mediators in non-proliferative SW982 synovial cell
It has studied in (converging after 3 days) the SW982 cell for being proliferated, converging and breaking up, two kinds of cytokine TNFs and IL1 (SW982 is the cell of the synovial cell used in embodiments herein to the validity of inducer as proinflammatory mediators System).Based on the transcriptional level by qPCR, have evaluated matrix metalloproteinase (MMP1), interstitial adhesive molecule (ICAM), IL6, IL8, TNF and enzyme COX2.As a result it is shown in Figure 1A.Figure 1A shows apparent trend: comparing with IL1, TNF is more effectively to induce Agent；However, two kinds of cell factors are strong inducers for the proinflammatory mediators of institute's scope of assessment.Therefore, in following embodiment Used in model system there is clinical correlation for treating RA.
Embodiment 2
In SW982 cell, compound 2 is the potent inhibitor of arachidonic acid release.
In with and without the pretreated situation of inhibitor, by analyzing the arachidonic acid (AA) in response to TNF Release, we have evaluated the inhibition in SW982 cell.Compound 2 significantly reduces the release of the TNF- induction of AA, wherein IC50Value is about 1 μM.Compare the depression effect (Figure 1B) of compound 2 Yu ATK and SB203580.With other related inhibitors phases Than compound 2 significantly reduces (10ng/ml) release of arachidonic TNF- induction.
Compound 2 normalizes AA and discharges to basic horizontal, without reducing AA release simultaneously.
Embodiment 3
The PGE of TNF induction is adjusted by compound 1 and compound 22Induction
With the different length in TNF stimulation 12-48 hours ranges of SW982 cell.TNF stimulation induces increased PGE2It produces Amount, is clearly depicted in Fig. 2.Unexpectedly, however, this PGE2Generation can be dose-dependently by 1 He of compound The inhibition (under 2.5 μM > 100% inhibit) of compound 2.Fig. 3 A- Fig. 3 B shows compound 1 and compound 2 inhibits TNF respectively The PGE of induction2The IC of generation50The calculated result of value: about 630nM and about 430nM.
PGE2It is the important regulator of the inflammatory process in the joint RA.It is in Fig. 2 and Fig. 3 A- Fig. 3 B statistics indicate that, this The compound of invention will be suitable for treatment RA.
It was found that reducing in response to TNF stimulation and generating PGE by SW982 cell2Aspect, compound 2 and commercial suppression Preparation ATK is equally effective.Relative to SB203580, by PGE2Level is consumed to lower than basic release, and two kinds of inhibitor make PGE2Yield is reduced to basic horizontal.This depression effect of SB203580 is consistent with report before.
Embodiment 4
Compound 1 inhibits the IL8 of TNF- induction to generate
Synovial cell's proinflammatory mediators, such as IL8 are in joint, in cartilage cell, cartilage the two, and with autocrine side The important regulator of inflammatory reaction of the formula in synovial cell.Fig. 4 is shown to be passed through in the SW982 cell line stimulated with TNF The IL8 of ELISA monitoring is horizontal (Fig. 4).Fig. 4 shows the dose-dependent inhibition that the IL8 of the presentation of compound 1 is generated.
Embodiment 5
Compound through the invention adjusts the TNF induced activation of the transcription factor ESE-1 of NF-kB regulation
ESE-1 belongs to ETS transcription factor family, by about 85 amino acid highly conserved DNA binding domain (referred to as The domain ets) it is defined.Ets transcription factor has been displayed adjusting gene related with different function, including cell Proliferation and differentiation, thin Born of the same parents' cycle progression, angiogenesis and vicious transformation.It has been found that ESE-1 is that height raises in RA synovial tissue.ESE-1 is opened Mover includes the binding site for a variety of co-factors, although NF-kB is considered as essential mediator.
Fig. 5 shows the ESE-1 activation that compound 1 and compound 2 adjust TNF induction with dosage-dependent manner.As Control, including NF-kB inhibitor BAY-7082.
It is in Fig. 5 statistics indicate that compared with known NF-kB inhibitor BAY-7082, compound 1 and compound 2 are aobvious Show the adjusting of similar (if not preferable) ESE-1 expression.Compared in contrast with control, it is known that NSAID indoles beauty The poor adjusting of the ESE-1 expression of pungent display TNF induction.
Embodiment 6
Compound 2 influences the transcriptional regulatory of many genes relevant to inflammation and joint injury.
By quantitative RT-PCR, the expression of COX2, MMP and IL-8 are had evaluated, it is known that it is inflammation and/or joint injury Core.With 0.1x106The density of a cells/well and it is inoculated with 982 cell of SW in a manner of 6 holes, is then converged after reaching 2 days Serum starvation (serum-starved) after conjunction.Be not present or there are before being handled 24 hours under TNF, with and without Preincubated cells 2 hours in the case where inhibitor.Utilize Δ Δ Ct method (Δ Δ Ct=CtTarget-CtGAPDHt)Through treating-(CtTarget- CtGAPDH)Untreated, and relative to endogenous control (GAPDH), determine the poor (fold- of the multiple of the expression of target proinflammatory gene difference).Average value ± the SD of 3 independent experiments.
TNF stimulate 24 hours after, the information (massage) of IL-8, MMP and COX2 increase separately 90 times, 120 times and 11 times (table 2 and Fig. 6).Up-regulation is reduced when with 2 inhibitor pretreatment cell of compound, wherein 2 inhibitor of above compound Averagely inhibit the induction of IL-8 and COX2 information respectively of about 53%, about 58% (MMP3) and about 42%.
Table 2, in response to TNF and compound 2 gene expression variation
Embodiment 7
Compound 2 significantly reduces prostaglandin E2 synthesis.
Since compound 2 significantly reduces the release of AA, so next whether we have studied inhibit to be also reflected in AA is subsequently converted to PGE2In, PGE2It is the regulator that one kind of inflammatory and damage process is important in joint.
It was found that inhibitor of the invention can effectively reduce PGE2Yield.As a result it is shown in table 3.
Table 3
The evidence provided in the embodiment above clearly illustrates that inhibitor of the invention has treatment in the treatment of RA Potentiality.

Claims (1)

1. the compound or its salt of following formula is preparing the purposes in the drug for treating rheumatoid arthritis:
Wherein X is CF3。
CN201811592300.8A 2010-09-02 2011-09-01 Polyunsaturated long-chain ketone or its salt are preparing the purposes in the drug for treating rheumatoid arthritis Pending CN109893518A (en)

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